This invention relates to improving the response of the mammalian immune system and, more particularly, to the subcutaneous or oral administration of dehydroepiandrosterone as a human immune system up-regulator to protect against both DNA and RNA viral infections, such as coxsackievirus B4 (CVB4), herpes simplex type 2 (HSV2) and human immunodeficiency virus (HIV).
Virus infection, whether produced by retroviruses such as HIV, feline or Friend leukemia, is associated with prolonged immunosuppression, i.e., down regulation of the immune system. Other viruses, such as influenza or coxsackievirus have immunosuppressive effects of transient but significant clinical consequence.
The expression of virus, bacterial, fungal or parasitic disease is seen when immunosuppression provides the opportunity for infectious organisms to grow in the host. In this regard, it does not matter if the primary insult to immunity is viral, bacterial or the result of chemotherapy, radiation or severe stress.
In general, it has been thought that steroid hormones of adrenocortical origin, when administered at pharmacological doses, are immunosuppressive. T. R. Cupps and A. S. Fauci, Immunolo. Rev. 65, 133-155 (1982); H. N. Claman, Clin. Immunol. Allergy 4, 317-329 (1984); C. J. Grossman, Endocrine Reviews 5, 435-455 (1984); A. Goldien, in: Basic and Clinical Pharmacology, B. G. Katzung, ed. Third Edition, Norwalk, Conn., (Appleton & Lange 1987) pp. 449-460; and J. E. Parillo and A. S. Fauci, Annual Reviews of Pharmacology and Toxicology 19, 179-201 (1979).
Such immunosuppression is believed particularly evident with viral infections. E. D. Kilbourne and F. L. Horsfall, Proceedings: Society of Experimental Biology and Medicine 77, 135-138 (1951); B. G. Gatmaitan et al., J. Exp. Med. 131, 121-1136 (1970); and M. W. Rytel, J. Infect. Dis. 120. 379-382 (1969). For example, it has been shown that the administration of glucocorticoids results in higher viral tissue titers and increased symptomatology. D. L. Lynden and S. A. Huber, Cellular Immunol. 87, 462-472 (1984); E. S. Meek and B. Golden, in: Infectious Diseases, P. D. Hoeprich, ed. (Harper and Row Publ., New York 1972) pp. 1241-1242; B. I. Hollinger, in: Virology, B. N. Fields et al., eds. (New York, Raven Press 1985) pg. 1424; K. M. Johnson in: Virology, supra, pg. 1046; and D. L. Yirrell et al., Virol. 68, 2461-2464 (1987).
Dehydroepiandrosterone, also known as 3-beta-hydroxyandrost-5-en-17-one or dehydroiso-androsterone (referred to hereinafter as DHEA), is a 17-ketosteroid which is quantitatively one of the major adrenocortical steroid hormones present in the metabolism of humans and other mammals. M. E. Windholz, The Merck Index, Ninth Edition (1976); K. Diem and C. Lentner, Geigy Scientific Tables (1975); E. Barret-Connor et al., N.E.J.M. 315, 1519-1524 (1986). Although DHEA appears to serve as an intermediary in gonadal steroid synthesis, the primary physiological function of DHEA is unclear. It is known, however, that levels of this hormone begin to decline in the second decade of life reaching 5% of the original level in the elderly.
Clinically, DHEA has been used systemically and/or topically for psoriasis and has been used in the treatment of gout, hyperlipemia, and in post-coronary patients. W. Regelson et al., New York Academy of Sciences 518, 260-273 (1988). In animal models and in humans it has shown an antiobesity effect, and an anticarcinogenic action in animals. Comoare T. T. Yen et al., Lipids 12, 409 (1977); J. E. Nestler et al., J. Clinical Endocrinology and Metabolism 66, 57-61 (1988); articles by C. Lopez and B. T. Rouse, respectively, in: Immunobiology of Herpes Simplex Virus Infection; B. T. Rouse and C. Lopez, eds. (CRC Press, Boca Raton, Fla. (1984)) pp. 45-69, and 107-120, respectively; E. Henderson et al., Carcinogenesis 2, 683-686 (1981); and A. Schwartz in: Molecular Biology of Aging, A. D. Woodhead ed., Vol. 35 (Plenum Pub. Co., New York (1985)) pp. 181-191.
DHEA is still used clinically in Europe, in conjunction with estrogen as an agent to reverse menopausal systems and also has been used in the treatment of manic depression, schizophrenia, and Alzheimer's disease.
DHEA has also been studied clinically at 40 mg/kg/day in the treatment of advanced cancer and for its potential role in multiple sclerosis. Regelson, supra. Mild androgenic effects, hirsutism, and increased libido were the side effects observed. These side effects can be overcome by monitoring the dose and/or the use of analogs.
Regardless of the causes of immunosuppression, the ability of an agent to up-regulate the immune system would have profound consequences on improving host resistance against infection in both clinical and veterinary disease.